A ribosomal gene panel predicting a novel synthetic lethality in non-BRCAness tumors

作者：Chao Zhang, Chao Zhang, Qiang Guo, Lifeng Chen, Zheming Wu, Xiaojian Yan, Chengyang Zou, Qiuxue Zhang, Tian Fang, Tian Fang, Qunxian Rao, Yang Li, Shizhen Shen, Min Deng, Liewei Wang, Huanyao Gao, Jia Yu, Hu Li, Cheng Zhang, Cheng Zhang, Somaira Nowsheen, Jake A. Kloeber, Fei Zhao, Zhongqiu Lin, Chunbo Teng, Zhongqiu Lin, Kun Song, Shuzhong Yao, Liangqing Yao, Lingying Wu, Yong Zhang, Xiaodong Cheng, Qinglei Gao, Jian Yuan, Zhenkun Lou, Jin‐San Zhang · 发表于：Signal Transduction and Targeted Therapy · 年份：2023 · DOI：10.1038/s41392-023-01401-y · 被引用次数：22 · 研究领域：PARP inhibition in cancer therapy、DNA Repair Mechanisms、CRISPR and Genetic Engineering

Poly (ADP-ribose) polymerase (PARP) inhibitors are one of the most exciting classes of targeted therapy agents for cancers with homologous recombination (HR) deficiency. However, many patients without apparent HR defects also respond well to PARP inhibitors/cisplatin. The biomarker responsible for this mechanism remains unclear. Here, we identified a set of ribosomal genes that predict response to PARP inhibitors/cisplatin in HR-proficient patients. PARP inhibitor/cisplatin selectively eliminates cells with high expression of the eight genes in the identified panel via DNA damage (ATM) signaling-induced pro-apoptotic ribosomal stress, which along with ATM signaling-induced pro-survival HR repair constitutes a new model to balance the cell fate in response to DNA damage. Therefore, the combined examination of the gene panel along with HR status would allow for more precise predictions of clinical response to PARP inhibitor/cisplatin. The gene panel as an independent biomarker was validated by multiple published clinical datasets, as well as by an ovarian cancer organoids library we established. More importantly, its predictive value was further verified in a cohort of PARP inhibitor-treated ovarian cancer patients with both RNA-seq and WGS data. Furthermore, we identified several marketed drugs capable of upregulating the expression of the genes in the panel without causing HR deficiency in PARP inhibitor/cisplatin-resistant cell lines. These drugs enhance PARP inhibitor/cispl...